Separation using a membrane has been commonly employed for separating or condensing a specific solute from a multi-dispersion fluid consisting of a solvent and many types of solutes and/or dispersoids (hereinafter simply referred to as “solutes”). As the separation method, “size barrier separation” to separate a solute according to the size by producing pores with a specific size in the membrane and “charge barrier separation” to separate a solute using a charged membrane and causing the solute to electrically repulse according to charges possessed by the solute have been known. In addition, as the separation method using a membrane, methods utilizing the difference in properties exhibited by solutes when treated with a membrane such as the adsorption force, ion-exchange capacity, and solubility-dispersiblity have been known. These separation methods are widely used in industries for desalting, water processing, food and pharmaceutical manufacturing, gas separation, and the like.
Blood purification therapy is carried out as a medical treatment for removing various toxins accumulated in blood with an objective of improving diseases such as renal failure and hepatic failure. The method of separation using a membrane have been applied to the Blood purification therapy. The blood purification therapy has a long history in artificial kidneys used for treating chronic or acute renal failures. Various artificial kidney membranes using collodion flat membranes, hollow fiber membranes made from synthetic polymers, and the like have been put in to practice. A method utilizing a blood processing membrane with a larger pore diameter is also used for blood purification such as plasma exchange and fractionating blood plasma components.
These blood processing membranes for extracorporeal circulation include a dialysis membrane, filtration membrane, diafiltration membrane, and the like. Suppressing pore blockage due to adsorption of plasma proteins and preventing protein denaturation due to contact with the membrane are demanded first of all for blood processing using a separating membrane. To this end, it has been necessary to make the membrane surface including pores coming in contact with blood hydrophilic.
On the other hand, efficiently removing wastes from blood is essential for a dialysis separating membrane of artificial kidneys used for treating renal insufficiency diseases. In recent years, as a result of the process for identifying wastes to be removed and ascertaining substances causing various complications accompanying a long-term or short-term dialysis, the substances to be removed now include, in addition to low molecular weight compounds such as urea and ammonia that have been removed in conventional dialysis, low molecular weight plasma proteins such as β2-microglobulin (hereinafter referred to as β2MG) and advanced glycation end products (hereinafter referred to as AGE).
In view of this situation, various high performance blood processing membranes have been made commercially available. Major membrane materials include natural polymers such as regenerated cellulose and its modified product, cellulose polymers such as cellulose acetate, and synthetic polymers such as a polyacrylonitrile-based polymer, polymethylmethacrylate-based polymer, polyamide-based polymer, polysulfone-based polymer, and ethylene-vinyl alcohol copolymer.
In terms of the structure, membranes are broadly classified into homogeneous membranes with a dense structure as a whole and inhomogeneous (asymmetric) membranes consisting of a dense selective separating layer and a porous supporting layer. From the viewpoint of permeability, the latter membranes are more preferable due to the least permeation resistance and the capability of ensuring physical membrane strength by the supporting layer.
Among these, a hydrophobic aromatic polysulfone-based polymer is gaining its position as a representative membrane material in recent years due to the versatility as a resin material, strength as a structural material, resistance to sterilization treatment with heat or radiation, and superior controllability of the pore diameter and membrane structure when manufacturing the membrane. However, since the aromatic polysulfone-based polymer is highly hydrophobic and, therefore, affects the blood clotting system, deaeration, and the like, this polymer is blended with hydrophilic polyvinyl pyrrolidone (hereinafter referred to as PVP) for use as a hollow separating membrane. This membrane has been regarded to be free from the complement activity that has been reported to occur when an untreated cellulose membrane comes into contact with blood and from the physiological activity harmful to the human body such as anaphylaxis caused by bradykinin production that occurs under specific conditions during dialysis using a polyacrylonitrile membrane with negative charges.
The PVP-blend polysulfone membrane can be manufactured in a wet spinning process comprising extruding a dope blend of an aromatic polysulfone-based polymer and water soluble PVP from the outer cylinder of a cylindical nozzle, causing the spun material to come into contact with an aqueous coagulant to effect phase separation, and removing the phase containing a large amount of PVP formed by the phase separation from the system.
Although it is possible to control the average pore size on the membrane surface that comes into contact with blood by changing the composition of the aqueous coagulant in this method, the pore size distribution on the surface of the resulting separating membrane tends to become wide due to fluctuations in the PVP molecular weight distribution and the polymer concentration in the dope, the shear force when the dope is discharged, and the like. For this reason, when low molecular weight plasma proteins are removed at a high ratio using this separating membrane, albumin which is a plasma protein useful for the human body is unnecessarily removed.
In addition, since a part of PVP that remains in the resulting separating membrane must be removed using a large amount of solvent and taking a long period of time in the membrane manufacturing process to prevent elution from the membrane during blood processing. This poses serious problems in the manufacturing process such as a decrease in productivity and requirement for processing a large amount of waste liquid.
In an effort to overcome these drawbacks, a method for separating plasma proteins with different isoelectric points using a separating membrane with negatively charged groups introduced on the surface, simulating a renal glomerular basement membrane, has been investigated and developed. Okayama Medical Journal, Vol. 105, 317(1993) reports separation of three plasma proteins with a molecular weight in the range of 14,300-66,000 having different isoelectric points using a negatively charged membrane for dialysis made from an ethylene-vinyl alcohol copolymer with sulfonic acid groups introduced in the membrane surface. The report describes that the sieving coefficient for plasma proteins with different isoelectric points varies and permeation selectivity by negative charges can be improved by increasing the quantity of negative charges in the membrane.
Japanese Patent Application Laid-open No. 5-131125 discloses that a hemodialysis membrane made from a blend of a sulfonated aromatic polysulfone-based polymer and an aromatic polysulfone-based polymer exhibits a high sieving coefficient for β2MG and a low sieving coefficient for albumin at the same time. In this manner, ultrafilter membranes having negatively charged groups on the surface that comes into contact with blood are known to exhibit high selective permeability for plasma proteins.
However, as physiologically well known, negatively charged groups, when brought into contact with blood, activate the coagulation factor XII, one of the intrinsic clotting factors, and the resulting fragment XIIa activates the coagulation factor XI in the presence of high molecular weight kininogen (e.g. E. Cenni, et al. “Biomaterials and Bioengineering Handbook” Chap. 8, 205, D. L. Wise ed., Mercel Dekker, New York, (2000) and Kidney Int. 1999 March 55(3) 11097-103). This activation acts as a trigger to activate the cascade for the intrinsic blood clotting system. The factor XIIa converts prekallikrein into kalliklein, which acts on high molecular weight kininogen to produce bradykinin (hereinafter abbreviated to BKN). The produced BKN induces an anaphylactoid reaction such as a slight fever and anesthesia of fingers and lips, when used in hemodialysis treatment. Therefore, direct contact of negatively charged groups with blood must be avoided in hemodialysis.
Japanese Patent Application Laid-open No. 8-505311 discloses a method for suppressing production of bradykinin using a membrane made from a polymer blend of a non-sulfonated polysulfone-based polymer and a sulfonated aromatic polysulfone-based polymer, wherein the product of the sulfonation degree of the sulfonated polysulfone-based polymer and the content of the sulfonated polysulfone-based polymer in the blend is 100 or less. However, use of this method of reducing the total sulfonic acid residues results in a decrease in the selective permeability of proteins, which is inevitably accompanied by a decrease in the cut off performance. In addition, the degree of the bradykinin production control disclosed in the patent application is simply lower than in the case where the polymer blend contains a large amount of sulfonated polysulfone. This does not necessarily indicate that the amount of bradykinin production is decreased to the extent not affecting the living body. Specifically, it is not known whether or not the amount of bradykinin production is a level safe for use in artificial kidneys.
Japanese Patent Application Laid-open No. 11-313886 discloses a method of using a neutral or cationic polymer for a semipermeable membrane for dialysis based on a negatively charged polyacrylonitrile to prevent activation of blood or plasma when coming in contact with the semipermeable membrane. Because negative charges on the pore surfaces all over the membrane are covered with a neutral or cationic polymer in this method, the amount of bradykinin production after the treatment is expected to decrease. However, the membrane does not have sufficient fractionation performance due to small negative charges of the semipermeable membrane for dialysis using the polyacrylonitrile as a base material.
In this manner, any conventional methods cannot provide a separating membrane having a sufficient cut off performance, while suppressing side effects on biological systems due to direct contact of the negatively charged groups with blood.